RESUMO
In this article, the derivatives of 3-quinoline carboxylic acid were studied as inhibitors of protein kinase CK2. Forty-three new compounds were synthesized. Among them 22 compounds inhibiting CK2 with IC50 in the range from 0.65 to 18.2 µM were identified. The most active inhibitors were found among tetrazolo-quinoline-4-carboxylic acid and 2-aminoquinoline-3-carboxylic acid derivatives.
Assuntos
Ácidos Carboxílicos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Caseína Quinase II/metabolismo , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
In order to find the new potent CK2 inhibitors the 60 derivatives of 2-aminopyrimidinone and their 6-aza-substituted analogs were synthesized and tested in vitro. Among them, the most efficient inhibitor 2-hydroxy-5-[4-(4-methoxyphehyl)-6-oxo-1,6-dihydropyrimidin-2-ylamino] benzoic acid was identified (IC50 = 1.1 µM). The structure--activity relationship study of newly synthesized derivatives was carried out and their binding mode with adenosine triphosphate-acceptor site of CK2 was proposed.
Assuntos
Ácidos Aminossalicílicos/farmacologia , Compostos Aza/farmacologia , Caseína Quinase II/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinonas/farmacologia , Ácidos Aminossalicílicos/síntese química , Ácidos Aminossalicílicos/química , Compostos Aza/síntese química , Compostos Aza/química , Caseína Quinase II/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-AtividadeRESUMO
The synthesis and in vitro evaluation of 40 new 2-phenylisothiazolidin-3-one-1,1-dioxide derivatives are described. The optimization based on biological screening data and molecular modeling resulted in a 10-fold increase in inhibitory activity compared with previously reported inhibitors of this class and led to the identification of 3-{[2-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-2-yl)benzoyl]amino}benzoic acid, a potent inhibitor of human protein kinase CK2 (ÐC50 = 1.5 µM).
Assuntos
Trifosfato de Adenosina/química , Antineoplásicos/química , Caseína Quinase II/antagonistas & inibidores , Óxidos S-Cíclicos/química , Inibidores de Proteínas Quinases/química , Bibliotecas de Moléculas Pequenas/química , meta-Aminobenzoatos/química , Antineoplásicos/síntese química , Caseína Quinase II/química , Domínio Catalítico , Óxidos S-Cíclicos/síntese química , Desenho de Fármacos , Ensaios Enzimáticos , Ensaios de Triagem em Larga Escala , Humanos , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Conformação Proteica , Inibidores de Proteínas Quinases/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade , Interface Usuário-Computador , meta-Aminobenzoatos/síntese químicaRESUMO
Apoptosis signal-regulating kinase 1 (ASK1) has recently emerged as an attractive therapeutic target for the treatment of cardiac and neurodegenerative disorders. The selective inhibitors of ASK1 may become important compounds for the development of clinical agents. We have identified the ASK1 inhibitor among 3H-naphtho[1,2,3-de]quinoline-2,7-diones using receptor-based virtual screening. In vitro kinase assay revealed that ethyl 2,7-dioxo-2,7-dihydro-3H-naphtho[1,2,3-de]quinoline-1-carboxylate (NQDI-1) inhibited ASK1 with a K(i) of 500 nM. The competitive character of inhibition is demonstrated in Lineweaver-Burk plots. In our preliminary selectivity study this compound exhibited strong specific inhibitory activity toward ASK1.
